Greater Annual Decline Research Articles

Bronchodilator responsiveness in children with primary ciliary dyskinesia.

Reversible airway obstruction is common in children with primary ciliary dyskinesia. However, the diagnostic value of adding bronchodilator (BD) response testing to routine spirometry is unclear. This is a retrospective analysis of pulmonary function test results obtained from children with primary ciliary dyskinesia seen as outpatients at the Hospital for Sick Children, Toronto. Spirometry results were collected for every appointment with BD response testing ("Visit", with pre-BD and post-BD measurements) as well as for the previous ("Baseline") and following ("Follow-up") encounters. A positive BD response was seen in 86 out of 474 (18.1%) of the pulmonary function tests from 82 children with primary ciliary dyskinesia. BD responsiveness was associated with a significant absolute change (±sd) in % predicted forced expiratory volume in 1 s (FEV1) from Baseline to Visit pre-BD (-6.5±10.3%, p<0.001), but not from Baseline to Follow-up (0.4±10.8, p=0.757). Antimicrobial therapy was initiated more commonly following a Visit with a positive BD response (OR 3.8, 95% CI 2.2-6.6) compared to no BD response. Children with a positive BD response had a greater annual decline in FEV1 % predicted compared to those with no BD response (-0.9% per year versus -0.5% per year, p<0.001). The annual decline in FEV1 % predicted was greater in children with multiple compared to one measured positive BD responses (-1.3% per year versus -0.6% per year, p<0.001) and in those not treated with antibiotic therapy following a positive BD response compared to those treated with antibiotics (-1.1% versus -0.6%, p<0.001). A positive BD response in children with primary ciliary dyskinesia may help identify those at risk for accelerated lung disease progression.

Dynamic Prediction of Pulmonary Hypertension in Systemic Sclerosis Using Landmark Analysis.

Pulmonary hypertension (PH) is a serious complication of systemic sclerosis (SSc). In this study, we explored the prediction of short-term risk for PH using serial pulmonary function tests (PFTs) and other disease features. SSc patients in whom disease onset occurred ≥10 years prior to data retrieval and for whom autoantibody specificity and PFT data were available were included in this study. Mixed-effects modeling was used to describe changes in PFTs over time. Landmarking was utilized to include serial assessments and stratified Cox proportional hazards regression analysis with landmarks as strata was used to develop the PH prediction models. We analyzed data from 1,247 SSc patients, 16.3% of whom were male and 35.8% of whom had diffuse cutaneous SSc. Anticentromere, antitopoisomerase, and anti-RNA polymerase antibodies were observed in 29.8%, 22.0%, and 11.4% of patients, respectively, and PH developed in 13.6% of patients. Over time, diffusing capacity for carbon monoxide (DLco) and carbon monoxide transfer coefficient (Kco) declined in all SSc patients (up to 1.5% per year) but demonstrated much greater annual decline (up to 4.5% and 4.8%, respectively) in the 5-7 years preceding PH diagnosis. Comparisons between multivariable models including either DLco, Kco, or forced vital capacity (FVC)/DLco ratio, demonstrated that both absolute values and change over the preceding year in those measurements were strongly associated with the risk of PH (hazard ratio [HR] 0.93 and 0.76 for Kco and its change; HR 0.90 and 0.96 for DLco and its change; and HR 1.08 and 2.01 for FVC/DLco ratio and its change; P < 0.001 for all). The Kco-based model had the greatest discriminating ability (Harrell's C-statistic 0.903). Our findings strongly support the importance of PFT trends over time in identifying patients at risk of developing PH.

PS-BPC11-3: INVESTIGATION OF THE EFFECT OF VISCERAL FAT ON THE CHRONIC KIDNEY DISEASE DEVELOPMENT AND PROGRESSION IN MEDICAL CHECKUP PARTICIPANTS

Objective: Many factors including obesity were reported as risk factors for development and progression of chronic kidney disease (CKD). However, there is a possibility that the effects of risk factors on the progression of renal dysfunction in CKD patients and the development of CKD are different. We aimed to evaluate the relationships of visceral fat area (VFA) and changes in kidney function in medical checkup participants stratified by the presence of CKD for investigation of the effect of visceral fat on CKD development and progression. Design and method: Study design: Retrospective cohort study. Setting: Routine medical checkups at two medical examination centers in Takeda Hospital Group. Participants: Subjects who underwent VFA measurements during medical checkups in 2012. The follow-up period was from April 2012 to March 2018. Exposures: VFA (≧ 100 cm2). Main outcomes: Changes in estimated glomerular filtration rate (eGFRcr). Statistical analysis: The relationships between VFA and eGFRcr were evaluated using a linear mixed effects model in the participants stratified by the presence of CKD. We defined CKD as eGFR &lt; 60 mL/min/1.73 m2 in this study. Results: Analysis was performed on total 2,753 subjects (age [mean ± SD] 50.3 ± 10.0 years). The non-CKD group was composed of 2,516 subjects (age 49.5 ± 9.67 years, 1,277 men, 1,239 women), and the CKD group was composed of 237 subjects (age 59.5 ± 8.48 years, 142 men, 95 women). In the total subjects the VFA ? 100 cm2 group exhibited a larger annual difference in eGFRcr compared to the &lt; 100 cm2 group (-0.24 mL/min/1.73 m2, p = 0.03). Although the difference of annual eGFRcr change in the non-CKD group was not statistically significant, VFA? 100 cm2 was associated with larger annual declines in eGFRcr in both CKD and non-CKD groups as compared to VFA &lt; 100 cm2 (-0.64 mL/min/1.73 m2, p = 0.01, and -0.20 mL/min/1.73 m2, p = 0.10). Conclusions: In the CKD group VFA ≧ 100 cm2 was significantly associated with a greater annual decline in eGFRcr. This significant difference of eGFRcr decline in the CKD group suggests the effect of visceral fat as a modifiable risk factor for CKD progression.

The Association Between Injurious Falls and Older Adults' Cognitive Function: The Role of Depressive Mood and Physical Performance.

BackgroundThe impact of falls on cognitive function is unclear. We explored whether injurious falls are associated with cognitive decline in older adults, and evaluated the role of changes in psychological and physical health as mediators of such association.MethodsThis prospective study involved 2267 community-dwelling participants in the Swedish National study on Aging and Care in Kungsholmen (≥60 years). Data on injurious falls (ie, falls requiring medical attention) during each 3-year time interval of follow-up were obtained from national registers. Assessment of cognitive function (Mini-Mental State Examination), depressive mood (Montgomery-Åsberg Depression Rating Scale), and physical performance (walking speed) were carried out every 3 or 6 years over a 12-year follow-up. The association between falls and cognition was estimated through linear mixed-effects models, and the mediating role of changes in depressive mood and physical performance was tested using mediation analysis.ResultsAfter adjusting for potential confounders, individuals who experienced injurious falls had a greater annual decline in Mini-Mental State Examination in the subsequent time interval (β = −1.49, 95% CI: −1.84; −1.13), than those who did not. The association increased with the occurrence of ≥2 falls (β = −2.13, 95% CI: −2.70; −1.56). Worsening of walking speed and depressive mood explained around 26% and 8%, respectively, of the association between falls and cognitive decline.ConclusionsInjurious falls are associated with greater cognitive decline, and this association is partly mediated by worsening of physical performance and, in a lesser extent, of depressive mood. These findings suggest that physical deficits and low mood are potential therapeutic targets for mitigating the association between falls and cognitive decline.

Initiation and adherence to adjuvant endocrine therapy among urban, insured American Indian/Alaska Native breast cancer survivors.

It has been shown that racial/ethnic disparities exist with regard to initiation of and adherence to adjuvant endocrine therapy (AET). However, the relationship among American Indian/Alaska Native (AIAN) individuals is poorly understood, particularly among those who reside in urban areas. We evaluated whether AET initiation and adherence were lower among AIAN individuals than those of other races/ethnicities who were enrolled in the Kaiser Permanente of Northern California (KPNC) health system. We identified 23,680 patients from the period 1997 to 2014 who were eligible for AET (first primary, stage I-III, hormone receptor-positive breast cancer) and used KPNC pharmacy records to identify AET prescriptions and refill dates. We assessed AET initiation (≥1 filled prescription within 1 year of diagnosis) and AET adherence (proportion of days covered ≥80%) every year up to 5 years after AET initiation. At the end of the 5-year follow-up period, 83% of patients were AET initiators, and 58% were AET adherent. Compared with other races/ethnicities, AIAN women had the second-lowest rate of AET initiation (non-Hispanic Black [NHB], 78.0%; AIAN, 78.6%; Hispanic, 83.0%; non-Hispanic White [NHW], 82.5%; Asian/Pacific Islander [API], 84.7%), the lowest rate of AET adherence after 1 year and 5 years of follow-up (70.3% and 50.8%, respectively), and the greatest annual decline in AET adherence during the 4- to 5-year period of follow-up (a 13.8% decrease in AET adherence [from 64.6% to 50.8%]) after initiation of AET. In adjusted multivariable models, AIAN, Hispanic, and NHB women were less likely than NHW women to be AET adherent. At the end of the 5-year period, total underutilization (combining initiation and adherence) in AET-eligible patients was greatest among AIAN (70.6%) patients, followed by NHB (69.6%), Hispanic (63.2%), NHW (58.7%), and API (52.3%) patients, underscoring the AET treatment gap. Our results suggest that AET initiation and adherence are particularly low for insured AIAN women.

Serum uric acid and renal survival prognosis in primary glomerulonephritis patients in a retrospective single-center cohort

Introduction: The role of serum uric acid (SUA) concentration in primary glomerulonephritis (PGN) aggravation is currently under active discussion. Objectives: This study primarily aimed to analyze the association between SUA concentration and renal survival prognosis in PGN patients and secondarily to determine whether hyperuricemia is an independent risk factor for reduced glomerular filtration rate (GFR) in the presence of nephrotic syndrome. Patients and Methods: We performed a retrospective observational single-center study involving 344 patients with biopsy-proved or clinically diagnosed PGN with the mean follow-up period of 5.3 [3.8-6.2] years. The rate of annual decline in estimated GFR (eGFR) was used to assess chronic kidney disease progression. Primary outcome measures were eGFR decline or transfer to renal replacement therapy (RRT) during the 5-year follow-up period. Results: There were 78/344 (22.7%) patients who eventually progressed to eGFR &lt;15 mL/min/1.73 m2 or started RRT. In multivariate logistic regression analysis eGFR at diagnosis, proteinuria and hyperuricemia were associated with increased renal risk in PGN patients during the 5-year follow-up period. However, a less significant effect of SUA on rapid eGFR decline was found in the patients with nephrotic-range proteinuria compared with the patients with mild proteinuria. Conclusion: Our study revealed that a higher level of SUA was significantly associated with a greater annual decline in GFR and, consequently, a worse 5-year renal survival prognosis in PGN patients. The effect of hyperuricemia on the risk of rapid CKD progression was greater in PGN patients with mild proteinuria compared with the patients with nephrotic-range proteinuria.

Olfaction and Changes in Body Composition in a Large Cohort of Older U.S. Adults.

Poor sense of smell in older adults may lead to weight loss, which may further contribute to various adverse health outcomes. However, empirical prospective evidence is lacking. We aimed to longitudinally assess whether poor olfaction is associated with changes in body composition among older adults. A total of 2,390 participants from the Health ABC Study had their olfaction assessed using the Brief Smell Identification Test in 1999-2000. Based on the test score, olfaction was defined as poor (0-8), moderate (9-10), or good (11-12). Total body mass, lean mass, and fat mass were measured by dual-energy X-ray absorptiometry annually or biennially from 1999 to 2007. At baseline, compared to participants with good olfaction, those with poor olfaction weighed on average 1.67 kg less (95% CI: -2.92, -0.42) in total mass, 0.53 kg less (95% CI: -1.08, 0.02) in lean mass, and 1.14 kg less (95% CI: -1.96, -0.31) in fat mass. In longitudinal analyses, compared to participants with good olfaction, those with poor olfaction had a greater annual decline in both total mass (-234 g, 95% CI: -442, -26) and lean mass (-139 g, 95% CI: -236, -43). They also tended to have a greater annual loss of fat mass (-113 g, 95% CI: -285, 59), but the difference was not statistically significant. Our results indicate poor olfaction is associated with lower body weight and greater weight loss in older adults. It is imperative for future studies to investigate potential underlying mechanisms and associated adverse health consequences.

Dietary inflammatory index and the aging kidney in older women: a 10-year prospective cohort study.

Chronic inflammation plays a role in the pathogenesis of age-related renal disease and the diet can moderate systemic inflammation. The primary objective of this study was to examine the associations between a dietary inflammatory index (DII®) score and renal function, the trajectory of renal function decline, and renal disease-related hospitalizations and/or mortality over 10years. The study was conducted in 1422 Western Australian women without prevalent chronic kidney disease and aged ≥ 70years. Baseline dietary data, obtained from a validated food frequency questionnaire, were used to calculate a DII score for each individual. In this cohort, the mean [range] DII score was 0.19 [- 6.14 to 6.39]. A higher DII score was associated with poorer renal function at baselineand a greater renal function decline over 10years; after multivariable adjustments, a one-unit higher DII score was associated with a 0.55mL/min/1.73m2 lower eGFR at baseline (p = 0.01) and a 0.06mL/min/1.73m2 greater annual decline in eGFR over 10years (p = 0.05). Restricted cubic splines provide evidence of a non-linear association between baseline DII score and risk of a renal disease-related event. Compared to participants in the lowest quintile, those in the highest quintile of DII score were at a higher risk of experiencing a renal disease-related event (adjusted HR 2.06, 95% CI 0.97, 4.37). Recommending an increased consumption of foods with a higher anti-inflammatory potential could form part of a multifaceted approach to reduce the risk of renal disease through diet and lifestyle changes.

Association Between Microinfarcts and Blood Pressure Trajectories

Cerebral microinfarcts are associated with increased risk of cognitive impairment and may have different risk factors than macroinfarcts. Subcortical microinfarcts are associated with declining blood pressure (BP) in elderly individuals. To investigate BP slopes as a risk factor for microinfarcts. From the population-based Mayo Clinic Study of Aging, 303 of 1158 individuals (26.2%) in this cohort study agreed to have an autopsy between November 1, 2004, and March 31, 2016. Cerebral microinfarcts were identified and classified as cortical or subcortical. Baseline and BP trajectories were compared for groups with no microinfarcts, subcortical microinfarcts, and cortical microinfarcts. A secondary logistic regression analysis was performed to assess associations of subcortical microinfarcts with midlife hypertension, as well as systolic and diastolic BP slopes. The presence of cerebral microinfarcts using BP slopes. Of the 303 participants who underwent autopsy, 297 had antemortem BP measurements. Of these, 177 (59.6%) were men; mean (SD) age at death was 87.2 (5.3) years. The autopsied individuals and the group who died but were not autopsied were similar for all demographics except educational level with autopsied participants having a mean of 1 more year of education (1.06; 95% CI, 0.66-1.47 years; P < .01). Among 297 autopsied individuals with antemortem BP measurements, 47 (15.8%) had chronic microinfarcts; 30 (63.8%) of these participants were men. Thirty (63.8%) had cortical microinfarcts, 19 (40.4%) had subcortical microinfarcts, and 4 (8.5%) had only infratentorial microinfarcts. Participants with microinfarcts did not differ significantly on baseline systolic (mean difference, -1.48; 95% CI, -7.30 to 4.34; P = .62) and diastolic (mean difference of slope, -0.90; 95% CI, -3.93 to 2.13; P = .56) BP compared with those with no microinfarcts. However, participants with subcortical microinfarcts had a greater annual decline (negative slope) of systolic (mean difference of slope, 4.66; 95% CI, 0.13 to 9.19; P = .04) and diastolic (mean difference, 3.33; 95% CI, 0.61 to 6.06; P = .02) BP. Subcortical microinfarcts were associated with declining BP. Future studies should investigate whether declining BP leads to subcortical microinfarcts or whether subcortical microinfarcts are a factor leading to declining BP.

Association between Cardiorespiratory Fitness and Lung Health from Young Adulthood to Middle Age.

Beyond the risks of smoking, there are limited data on factors associated with change in lung function over time. To determine whether cardiorespiratory fitness was longitudinally associated with preservation of lung health. Prospective data were collected from 3,332 participants in the Coronary Artery Risk Development in Young Adults study aged 18-30 in 1985 who underwent treadmill exercise testing at baseline visit, and 2,735 participants with a second treadmill test 20 years later. The association between cardiorespiratory fitness and covariate adjusted decline in lung function was evaluated. Higher baseline fitness was associated with less decline in lung function. When adjusted for age, height, race-sex group, peak lung function, and years from peak lung function, each additional minute of treadmill duration was associated with 1.00 ml/yr less decline in FEV1 (P < 0.001) and 1.55 ml/yr less decline in FVC (P < 0.001). Greater decline in fitness was associated with greater annual decline in lung function. Each 1-minute decline in treadmill duration between baseline and Year 20 was associated with 2.54 ml/yr greater decline in FEV1 (P < 0.001) and 3.27 ml/yr greater decline in FVC (P < 0.001). Both sustaining higher and achieving relatively increased levels of fitness over 20 years were associated with preservation of lung health. Greater cardiopulmonary fitness in young adulthood, less decline in fitness from young adulthood to middle age, and achieving increased fitness from young adulthood to middle age are associated with less decline in lung health over time. Clinical trial registered with www.clinicaltrials.gov (NCT 00005130).

Determinants of annual change in physical activity in COPD.

Daily physical activity (PA) is reduced in patients with COPD. Previous cross-sectional analyses indicate various predictors for a low level of PA including airway obstruction, exacerbations and co-morbidities. However, information from longitudinal studies evaluating PA in the context of disease progression, survival and co-morbidities is scant. In a heterogeneous cohort of COPD patients, we annually assessed the number of steps per day over 1 week and potential determinants including lung function, exacerbations and co-morbidities. Univariable and multivariable mixed effect models were used to investigate associations between the change in steps per day (dependent variable) and possible predictors and their annual changes. A total of 177 COPD patients (46% GOLD (Global Initiative for Chronic Obstructive Lung Disease) stage 1/2, 38% stage 3 and 16% stage 4) with a mean (min/max) follow-up time of 2.7 (1/5) years were annually assessed. The number of steps per day decreased significantly over time (P < 0.001) with a mean annual change of -508 steps. The decrease in activity was significantly associated with forced expiratory volume in 1 s (FEV1 ) % predicted (P = 0.020) but not with annual changes in FEV1 . Hyperinflation, exacerbations, co-morbidities and their annual changes, and survival did not significantly affect change in PA. COPD patients have a substantial decrease of PA over time. This decrease seems to be determined by the degree of airflow limitation. However, patients with a greater annual decline in lung function did not show a greater decrease in PA. The rate of decline in PA did not differ between survivors and non-survivors in this cohort.

Asthma exacerbations and lung function in patients with severe or difficult-to-treat asthma

Asthma exacerbations and lung function in patients with severe or difficult-to-treat asthma

Type 2 Diabetes and Cognitive Decline Over 14 Years in Middle-Aged African Americans and Whites: The ARIC Brain MRI Study

Background: Diabetes predicts late-life dementia, but the association with rate of cognitive decline is inconsistent and has rarely been examined in non-white populations, despite the high prevalence of diabetes in African Americans. We evaluated the effect of diabetes on cognitive decline in middle-aged African Americans and whites. Methods: Atherosclerosis Risk in Communities (ARIC) Brain MRI Study participants (n = 1,886, mean age = 60, 49% African American) underwent assessments of verbal memory, processing speed, and verbal fluency four times over 14 years. Using race-stratified mixed linear effects models, we examined cognitive change for participants with prevalent (baseline) diabetes and incident (diagnosed after baseline) diabetes versus those without diabetes. Results: African Americans had more advanced diabetes, as indicated by fasting blood glucose levels, anti-diabetes medication use, and cardiovascular risk profiles. African Americans with prevalent diabetes experienced 41% greater annual decline in processing speed scores (p = 0.048) and 50% greater annual decline in verbal fluency scores (p = 0.042) than those without diabetes; incident diabetes was not associated with cognitive decline. Among whites, diabetes was not associated with cognitive decline. Conclusions: Prevalent diabetes was associated with greater cognitive decline in middle-aged African Americans, possibly reflecting adverse effects of longer duration and more advanced diabetes. i 2014 S. Karger AG, Basel

Long-Term Renal Function of Living Kidney Donors- A Prospective Cohort Study.

Introduction and Aims: The long-term medical risks after living kidney donation are uncertain. This study aimed to determine the factors that predict long-term post-donation decline in renal function amongst living kidney donors. Methods: A longitudinal analysis was undertaken within a prospective cohort of living donors (n=357, aged above 22.2 years) donated in a single centre between January 2000 and December 2013. The change in estimated glomerular filtration rate (eGFR) between baseline (pre-donation), one, five and ten years was analysed using multilevel mixed model analyses. The glomerular filtration rate was estimated using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formula. Results: Of the 357 living donors, 338 (94.7%) completed follow-up at the first year. A total of 138 (out of 237, 58.2%) and 48 (out of 88, 54.5%) were followed at five and ten years, respectively. The mean eGFR at baseline, one, five and ten years were 94 ml/min/1.73m2 (SD: 13.97), 61 (SD: 12.45), 58 (SD: 12.81) and 56 (SD: 12.67). Overall, eGFR declined by 32.7 (SD: 10.7) ml/min/1.73m2 between baseline and one year in participants who had repeated measures of serum creatinine (323 out of 357, 90.5%). The decline in eGFR stabilised between 1-5 and 5-10 years after donation, with a median reduction in eGFR of 0.47 (SD: 6.1) ml/min/1.73m2 and 0.81 (SD: 3.1) ml/min/1.73m2, respectively. Multivariate linear mixed modelling suggested that older age and higher body mass index (BMI) at the time of donation were associated with the greatest annual decline in eGFR post-nephrectomy (p values <0.001 and 0.02 respectively). There was a 0.57 ml/min/1.73m2 per year reduction in eGFR for every year increase in age at the time of donation. For every 1 kg/m2 increase in BMI at the time of donation, there was a 0.70 ml/min/1.73m2 reduction in eGFR annually over the 10-year follow-up. There was an insufficient number of donors with pre-existing hypertension and/or albuminuria to assess an effect on eGFR. Conclusion: Older age and higher BMI at the time of donation are independent predictors of decline in renal function over time amongst living kidney donors. However, the absolute decrement of renal function appeared to remain stable with aging.

Changes in forced expiratory volume in 1 second over time in patients with controlled asthma at baseline

A predominant feature of asthma is an accelerated rate of decline in forced expiratory volume in 1s (FEV1), but data on the variability and factors associated with this change in patients with controlled asthma are largely unknown. 140 patients with controlled asthma were enrolled based on the Global Initiative for Asthma guidelines. We examined the data of a prospective analysis of the association between asthma control and change in FEV1 over time. A 3-year follow-up assessment was completed in 128 patients. The mean rate of change in FEV1 was a decline of 22.2mLyr(-1), with significant variation in the levels of change. The between patient standard deviation for the rate of decline was 34.1mLyr(-1). We next classified the subjects of less than the 25th percentile as rapid decliners, and greater than the 25th percentile as non-rapid decliners. The decrease in the Asthma Control Test score over a 3-year period was higher for rapid decliners than that for non-rapid decliners (p<0.001). The rapid decliner was more likely to be older, to have higher levels of FeNO, and to have had severe exacerbations during the study. Patients with severe exacerbations had a greater annual decline in FEV1 compared to patients with no exacerbations (-13.6 vs. -53.2mLyr(-1), p<0.0001). Among patients with controlled asthma at baseline, the rate of change in FEV1 is highly variable. Severe exacerbations are strongly associated with a rapid loss of lung function.

Longitudinal Changes in Pulmonary Function of Asbestos Workers

To observe the longitudinal changes in pulmonary function associated with exposure to asbestos in a group of highly exposed workers. Pulmonary diffusing capacity (DLco) and spirometry of 243 Chinese asbestos workers were measured and remeasured after 5 and 10 yr. Their annual changes in relation to cumulative asbestos exposure and asbestosis were determined using multivariate analysis. The greatest annual decline was observed in DLco, particularly in workers with asbestosis, followed by FVC and FEV(1). A greater decline in DLco accorded with a higher level of cumulative asbestos exposure. A similar trend was also seen in FVC, in which the highest exposure level was associated with 223 ml loss over each 5 yr period or 45 ml/yr. There were substantial declines in DLco and FVC over time in the asbestos workers, and a dose-response trend between asbestos exposure and accelerating functional loss.

Tumor Necrosis Factor–α rs361525 Polymorphism Is Associated with Increased Local Production and Downstream Inflammation in Chronic Obstructive Pulmonary Disease

Chronic obstructive pulmonary disease (COPD) has a genetic component, explaining susceptibility. Tumor necrosis factor (TNF)-alpha polymorphisms have been associated with COPD, but it is unclear if genotype influences clinical phenotype, protein expression, and bioactivity. To determine if a functional polymorphism was important by assessing TNF-alpha expression and activity and its association with clinical severity over time. Patients with COPD with rs361525 polymorphism were matched to patients with COPD without rs361525 polymorphism. TNF-alpha, its antagonists, and downstream mediators were measured in plasma and sputum. To determine TNF-alpha bioactivity, IL-8 secretion from primary bronchial epithelial cells (PBECs) was measured, and neutrophil migration was assessed using sputum from both subject groups in the presence and absence of TNF-alpha antibody. Subjects were followed annually and compared. Patients with polymorphism had more chronic bronchitis, a lower body mass index, and a greater annual decline in FEV(1) than patients with COPD without rs361525 polymorphism. TNF-alpha concentrations were 100-fold higher in airway secretions from the patients with the rs361525 polymorphism, with no difference in TNF-alpha antagonists. Their lung secretions contained more IL-8 and myeloperoxidase, consistent with downstream inflammation. Sputum from patients with rs361525 polymorphism induced greater secretion of IL-8 from PBECs and increased neutrophil migration. These effects could be abrogated by TNF-alpha antibody, demonstrating the bioactivity of TNF-alpha in lung secretions from this group. This TNF-alpha polymorphism is associated with clinical features of disease including progression. There is clear evidence of TNF-alpha overexpression and bioactivity with neutrophilic inflammation. The polymorphism is likely to be a factor that influences a COPD disease phenotype and its progression.

A Prospective Study of Albuminuria and Cognitive Function in Older Adults: The Rancho Bernardo Study

Chronic kidney disease is a risk factor for cognitive impairment. Albuminuria is an early manifestation of chronic kidney disease and a marker of endothelial dysfunction and vascular risk. Results of prior studies of albuminuria and cognitive function are contradictory. The authors studied 1,345 community-dwelling women and men in southern California (mean age, 75 years) at a 1992-1996 research clinic visit, when urine albumin/creatinine ratio (ACR) was measured in spot morning urine and cognitive function was evaluated by using the Mini-Mental State Examination Trail-Making Test B, and category fluency test. An ACR of > or =30 mg/g was found in 17% of women and 15% of men in 1992-1996. Analysis of covariance was used to compare cognitive function score by categorical ACR. Between 1999 and 2002, 759 participants returned for repeat cognitive function testing. For men, but not women, baseline albuminuria, but not estimated glomerular filtration rate, was associated with reduced cognitive function at follow-up on all tests (P's < 0.05). An ACR of > or =30 mg/g was associated with greater annual decline in Mini-Mental State Examination and category fluency scores. Albuminuria may be an easily measured marker predicting future cognitive function decline. Results imply a common underlying mechanism affecting the renal and cerebral microvasculature.

Change in Estimated GFR Associates with Coronary Heart Disease and Mortality

Kidney function predicts cardiovascular and all-cause mortality, but little is known about the association of changes in estimated GFR (eGFR) with clinical outcomes. We investigated whether 3- and 9-yr changes in eGFR associated with risk for coronary heart disease (CHD) and all-cause mortality among 13,029 participants of the Atherosclerosis Risk in Communities (ARIC) Study. After adjustment for baseline covariates including eGFR in Cox proportional hazards models, the quartile of participants with the greatest annual decline (annual decline > or =5.65%) in eGFR were at significantly greater risk for CHD and all-cause mortality (hazard ratio 1.30 [95% confidence interval 1.11 to 1.52] and 1.22 [95% confidence interval 1.06 to 1.41], respectively) compared with the third quartile (annual decline between 0.33 and 0.47%). We observed similar results when we analyzed 9-yr changes in eGFR. Adjustment for covariates at the second eGFR used to estimate change reduced the association with CHD but not with mortality. Among participants with stage 3 chronic kidney disease, an increase in eGFR during the first 3 yr also associated with a higher risk for mortality, perhaps as a result of clinical instability. In conclusion, a steeper than average decline in eGFR associates with a higher risk for CHD and all-cause mortality. Increases in eGFR among participants with chronic kidney disease associate with similar increased risks.

Severe exacerbations predict excess lung function decline in asthma

Severe asthma exacerbations are periods of intense airway inflammation that have been hypothesised to contribute to structural changes in the airways. If so, accelerated lung function decline over time should be more prevalent in adult patients with asthma who have frequent exacerbations than those without, but to date this has not been demonstrated. A cohort study was performed in order to investigate the effect of severe exacerbations on the progression of airway obstruction in 93 nonsmoking asthmatics with moderate-to-severe disease prior to treatment with inhaled corticosteroids. Subjects were followed for > or =5 yrs (median follow-up 11 yrs). In total, 56 (60.2%) subjects experienced at least one severe exacerbation (median rate 0.10.yr(-1)). Oral corticosteroid use and more severe airway obstruction at baseline were associated with a higher exacerbation rate. Independent of these variables, asthma patients with frequent exacerbations had a significantly larger annual decline in forced expiratory volume in one second (FEV(1); median difference (95% confidence interval) 16.9 (1.5-32.2) mL.yr(-1)). Exacerbation rate significantly predicted an excess decline in FEV(1), such that one severe exacerbation per year was associated with a 30.2 mL greater annual decline in FEV(1). These data support the hypothesis that exacerbations, indicating intermittent periods of worsening airway inflammation, are associated with excess lung function decline in asthma.